El Greco was among those artists most responsive to the religious fervor inspired by the Catholic Church during the Counter Reformation, and his work is characterized by the drama and passionate intensity with which he interprets theological ideas. Born in Crete, El Greco traveled to Venice between 1560 and 1567, where he absorbed the manner of Titian and Tintoretto. After an additional seven years spent in Rome, from 1570 to 1577, the artist eventually settled in the Spanish city of Toledo, where he established an immensely successful studio. With its elongated forms and narrow color range, Saint Francis in Prayer is typical of El Greco's endeavor to imbue his religious figures with a profound sense of spiritual struggle and painful redemption.

Saint Francis of Assisi (1182–1226), the founder of the Franciscan order, was a wealthy young man who renounced his riches and took a vow of chastity, obedience, and poverty. Here the saint prays humbly before the crucifix, meditating on death. The identifying attributes in this work are the friar's habit and the stigmata (wounds of Christ on his hands, feet, and side) which he received in a vision. The skull, a symbol of man's mortality, is pointedly juxtaposed with the crucifix, the symbol of man's salvation. While El Greco may have appropriated elements of Venetian Mannerism from Tintoretto, such as his figural elongations and acid colors, he nonetheless made the style his own by infusing Saint Francis with an extraordinary religious intensity.